The present invention describes methods for preventing or treating a variety of diseases and deleterious medical conditions associated with interleukin-1 (IL-1).
Cytokines are extracellular proteins that modify the behavior of cells, particularly those cells that are in the immediate area of cytokine synthesis and release. One of the most potent inflammatory cytokines thought to be a key mediatory in many diseases and medical conditions is IL-1. Interleukin-1 is manufactured, although not exclusively, by cells of the macrophage/monocyte lineage and is produced in two known forms, IL-1 alpha (IL-1.alpha.) and IL-1 beta (IL-1.beta.).
A disease or medical condition is considered an "interleukin-1 mediated disease" if the spontaneous or experimental disease or medical condition is associated with elevated levels of IL-1 in bodily fluids or tissue, or if cells or tissues taken from the body produce elevated levels of IL-1 in culture. In many cases, such IL-1 mediated diseases are also recognized by the following additional two conditions: (1) pathological findings associated with the disease or medical condition can be mimicked experimentally in animals by the administration of IL-1; and (2) the pathology induced in experimental animal models of the disease or medical condition can be inhibited or abolished by treatment with agents that inhibit the action of IL-1. In most IL-1 mediated diseases, at least two of these three conditions are met. Diseases or medical conditions that are IL-1 mediated include, for example, arthritis, inflammatory bowel disease, sepsis and septic shock, reperfusion injury, osteoporosis, asthma, insulin diabetes, myelogenous and other leukemias, psoriasis, cachexia/anorexia, multiple sclerosis, and ischemic injury, including cerebral infarctions such as cerebral palsy.
Arthritis is a chronic joint disease that afflicts and disables, to varying degrees, millions of people worldwide. The disease is typically characterized at the microscopic level by the inflammation of synovial tissue and by a progressive degradation of the molecular components constituting the joint cartilage and bone. Continued inflammation and erosion of the joint frequently lead to considerable pain, swelling, and loss of function. While the etiology of arthritis is poorly understood, considerable information has recently been gained regarding the molecular aspects of inflammation. This research has led to the identification of certain cytokines, which are believed to figure prominently in the mediation of inflammation. The involvement of interleukin-1 in arthritis has been implicated by two distinct lines of evidence. First, increased levels of interleukin-1 and of the mRNA encoding it have been found in the synovial tissue and fluid of arthritic joints. See G. Buchan et al., "Third Annual General Meeting of the British Society for Rheumatology," London, England, Nov. 19-21, 1988 J. Rheumatol. 25 (Supplement 2); Fontana et al., Rheumatology Int., 2:49-53 (1982); Duff et al., Monokines and Other Non-Lymphocytic Cytokines, M. Powanda et al., editors, pp. 387-392 (Alan R. Liss, Inc. 1988).
Second, the administration of interleukin-1 to healthy joint tissue has been shown on numerous occasions to result in the erosion of cartilage and bone. In one experiment, intraarticular injections of IL-1 into rabbits were shown to cause cartilage destruction in vivo as described by Pettipher et al., Proc. Nat'l Acad. Sci. U.S.A., 83:8749-8753 (1986). In other studies, IL-1 was shown to cause the degradation of both cartilage and bone in tissue explants. Relevant references include J. Saklatavala et al., Development of Diseases of Cartilage and Bone Matrix, pp. 291-298 (Alan R. Liss, Inc.) and Stashenko et al., The American Association of Immunologists, 183:1464-1468 (1987). One generally accepted theory used to explain the causal link between IL-1 and inflammation is that IL-1 stimulates various cell types, such as fibroblasts and chondrocytes, to produce and secrete proinflammatory or degradative compounds, such as prostaglandin E2 and collagenase.
Inflammatory bowel disease ("IBD") is a term used to describe both acute and chronic inflammatory conditions of the intestinal tract tissue and encompasses two generally distinct maladies known as ulcerative colitis and Crohn's disease. Ulcerative colitis is a mucosal ulceration of the colon. Crohn's disease, which is also referred to as ileitis, ileocolitis and colitis, is a transmural inflammation that can be found throughout the general intestinal tract.
IBD is characterized by various histological features including transmural acute and chronic granulomatous inflammation with ulceration, crypt abbesses and marked fibrosis. Not all of these indications, however, will be found in all IBD cases. Spontaneous reactivation, extraintestinal inflammation and anemia are often associated with IBD. Large joint arthritis is commonly found in patients suffering from Crohn's disease.
In the molecular processes of the inflammation associated with arthritis, research has found that various cytokines appear to mediate aspects of IBD. In particular, IL-1 has been implicated as a mediating material in IBD. Again, two distinct lines of evidence lead to this conclusion. Increased levels of IL-1 have been found in affected areas of intestines from patients with IBD. Tissues from patients with active ulcerative colitis showed IL-1 levels about 15 times the level found in control samples. Tissues with active Crohn's disease showed IL-1 levels about 6 times that of control, and tissues with inactive Crohn's disease were about three times that of the control tissue samples. See, Sartor et al., Gastroenterology, 94:A399; see also Satsangi et al., Clin. Exp. Immunol., 67:594-605 (1987); Rachmilewitz et al., Gastroenterology, 67:594-605 (1989)(the bioassay used to determine IL-1 concentration levels is known to also unselectively detect IL-2, IL-4, IL-6 and IL-7).
The role of IL-1 in IBD has also been implicated by studies that have shown that the perfusion of rabbit colons with IL-1 induces the production of prostaglandin and thromboxane. Comminelli et al., Gastroenterology, 97:1400-1405 (1989). This finding is consistent with the hypothesis described above, i.e., IL-1 is linked with the inflammation of tissues due to its stimulatory effect of producing proinflammatory or degradative compounds. Thus, it is likely that systemic and local IL-1 production initiates or contributes to the inflammatory response in IBD, and plays an active role in the pathogenesis of the disease. The systemic production of IL-1 may also be responsible, in part, for the extraintestinal inflammation associated with Crohn's disease.
Sepsis syndrome, referred to herein as "sepsis," is the systemic inflammatory response caused by microbial infection. For example, infections caused by the release of endotoxins by gram negative bacteria elicit the secretion of several cytokines including tumor necrosis factor alpha and IL-1. Sepsis, including septic shock and severe sepsis, is not caused directly by the invading microorganism. Rather, it is a result of an overwhelming cytokine response that induces pathologic changes in the host, including changes in thermoregulation, vascular permeability and resistance, cardiac function, bone marrow function, and the activity of key enzymes.
In the case of severe sepsis and septic shock, sepsis syndrome is characterized by periods of deteriorating organ function that may result in multiple organ dysfunction leading to death. Sepsis is the most common cause of death in intensive care units and statistics indicate that the incidence of the disease has substantially increased over the past decade. Septic shock for example, is characterized by various symptoms, including a drop in mean arterial blood pressure (MAP), a decrease in cardiac output, tachycardia, tachypnea, lacticacidemia and leukopenia. At present there are few treatment options for patients suffering from sepsis and septic shock, and the treatments available are generally supportive in nature rather than treatment for the pathologic condition.
That IL-1 may have a role in the mediation of sepsis and septic shock has been suggested by various studies. In one study of children suffering from gram-negative septicemia, elevated levels of IL-1 were found in 21% of the patients examined. In addition, it was shown that IL-1 serum levels were significantly higher in patients who died than in the survivors. Girardin et al., New Engl. J. Med., 319:397-400 (1988); see also, Cannon et al., Critical Care Medicine, S58 (April 1989)(abstract).
It has also been shown that human IL-1 induces a shock-like state in rabbits. A single bolus injection of human IL-1.beta. resulted in hypotension and several hemodynamic and hematological parameters characteristic of septic shock. For example, the mean arterial blood pressure of IL-1 injected rabbits decreased by a minimum of 19.1%. Okusawa et al., J. Clin. Inves., 81:1162-1171 (1988).
Ischemic injury may occur to a tissue or organ whenever that tissue or organ is deprived of its normal blood flow. Further damage may occur when the flow of oxygenated blood is restored to that tissue. The extent and reversibility of the damage imparted depends partly on the severity of the original insult. It is possible, however, to mitigate the extent of tissue damage resulting from reperfusion by a variety of therapeutic interventions. Simpson et al., "Oxygen Radicals and Tissue Injury," Brook Lodge Symposium - Upjohn (B. Halliwell, ed. 1988).
Reperfusion injury is a well documented sequela to ischemic episodes in the heart, gut, kidney, liver and other organs. Simpson et al., supra; Herman et al., FASEB J., 2:146-151 (1988); McDougal, J. of Urology, 140:1325-1330 (1988); Finn, Kidney Int., 7:171-182 (1990); Schrier, Klin. Wochenschr., 66:800-807 (1988); and Winchel, Transportation, 48:393-396 (1989). The exact pathogenesis of reperfusion injury may vary depending on the tissue affected. In the heart, for instance, reperfusion injury is accompanied by a dramatic influx of neutrophils, and these cells are thought to play a major role affecting the reperfusion damage (Lucchesi et al., Ann. Rev. Pharmacol. Toxicol., 26:201-224 (1988)). Renal ischemia and reperfusion injury, on the other hand, appear to involve an increase in tubular cell membrane permeability, increased levels of intracellular calcium, altered mitochondrial respiratory function, and the generation of free radicals. In the kidney, the role of extravasating neutrophils in affecting the reperfusion injury is less certain. McDougal, J. Urology, 140:1325-1330 (1988); Finn, Kidney Int., 37:171-182 (1990); Schrier, Klin. Wochenschr., 66:800-807 (1988); and Winchel, Transportation, 48:393-396 (1989).
Despite the differences in cellular participation during ischemia and reperfusion injury, there may be similarities in the underlying mechanism. IL-1 is recognized as an early stage mediator of organ injury, and may be generated by resident or newly infiltrated inflammatory cells giving rise to organ specific tissue pathology.
Current research in ischemia related brain disorders implicates enhanced synaptic release of excitatory amino acid neurotransmitters as a major contributor to brain injury. However, recent animal studies also suggest a possible role for certain cytokines as described, for example, in Relton & Rothwell, Brain Res. Bull., 29:243-246 (1992). In addition, increased levels of IL-1.beta. in cerebralspinal fluid have been detected in pathophysiological conditions including chronic relapsing experimental encephalomyelitis in guinea pig, bacterial meningitis in humans, patients with human immunodeficiency virus type-1 infection, Alzheimer's disease and in patients with head injuries. Furthermore, it has also been found that recombinant human IL-1.beta. when injected into the striatum of rats produced extensive neuronal damage with a loss of glutamic acid decarboxylase activity as described in Rothwell & Relton, Neurosci. Biobehav. Rev., 17:217-227 (1993). These studies indicate the involvement of the IL-1 receptor systems in the pathogenesis of ischemia related brain disorders, including cerebral palsy.
Cerebral palsy is a generic term defining a non-progressive static disturbance of motor function, present from birth or early life, caused by a discrete encephaloclastic insult to the central nervous system (CNS) during gestation, the perinatal period or infancy. Although most cases result from ischemic-hypoxic insults, infection, hemorrhage or trauma may occasionally result in the pathologic condition.
The lesions associated with cerebral palsy are predominantly caused by ischemic-hypoxic insults to the immature brain due to asphyxia. There are several types of cerebral palsy depending on the pattern, location and severity of the ischemic-hypoxic insult. For example, spastic diplegia results from ischemic-hypoxia necrotic lesions localized near the dorsolateral surfaces of the lateral ventricles believed to be an end-arterial zone in pre-term infants. More extensive ischemic-hypoxic insults produce significant cystic destruction of central white matter of the hemispheres (deep lesions) associated with quadriplegia and mental deficiency. Ischemic-hypoxic insults to term infants tend to affect the parasagittal and parietoccipital cortex watershed zone, hippocampus, thalamus, and cerebellar hemispheres (superficial lesions). Congenital hemiplegia results from arterial occlusion in the middle cerebral artery territory resulting in a pro-encephalic lesion of the hemisphere, or from a more diffuse and partial hemisphere insult. The extent of damage to the cerebral cortex has been correlated with an increased likelihood of seizures and abnormal intelligence. There are no known effective methods for treating cerebral palsy.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. MS is a progressive disease of adults characterized by relapses and remissions, often leading to progressive physical, cognitive and emotional impairment. Although the cause of MS is unknown, the pathological, genetic and immunological features of the condition have been identified and indicate that the disease has an autoimmune basis.
Studies have shown that IL-1 can augment the in vitro activation of encephalitogenic T lymphocytes and enhance adoptive transfer of experimental autoimmune encephalomyelitis (EAE). EAE is an acute or chronic relapsing inflammatory demyelinating disease of the CNS resulting from sensitization of genetically susceptible animals with neuroantigens such as myelin basic protein (MBP). EAE is an art-accepted and often used animal model for acute human MS. Evidence of the involvement of IL-1 in immune-mediated demyelination comes from in vivo EAE studies. These studies demonstrate that exogenous IL-1.alpha. can exacerbate the clinical severity and duration of the paralysis observed in the EAE animal model. Current treatment for MS include the use of steriods and more recently interferon .beta. (IF.beta.). Steriods, however, are known to have many deleterious side effects when administered over a period of time.
Accordingly, a need exists for an effective, yet selective, inhibitor or IL-1 for the treatment, amelioration or prevention of arthritis, IBD, sepsis and septic shock, ischemic injury, reperfusion injury, multiple sclerosis and ischemic brain injury such as cerebral palsy and generally for use in the treatment of inflammation. The present invention satisfies this need and provides related advantages as well.